Homeostatic platsicity in a thorny situation

Synapses, the connections between neurons can strengthen and weaken depending on the specific activity at that synapse. This is called synaptic plasticity, and we've talked about it a lot on this blog (here, here, here and here).

the strengthening and weakening of synaptic connections corresponds to the spine growing or shrinking (Matsuzaki 2007)

However, there is another kind of plasticity that can occur at synapses. This is called homeostatic plasticity. And instead of the synapse strengthening or weakening depending on the specific activity at that synapse, the synapses strengthen and weaken in homeostatic plasticity depending on the activity of the whole cell.

To drastically simplify, each cell 'wants' to fire about a certain amount, if it suddenly starts to fire a lot less, it will take steps to strengthen its connections or make itself more 'excitable' so it can get back to its preferred amount of firing. Similarly if the cell starts to fire a lot more than normal, it will take steps to make itself less excitable and to weaken its connections until it reaches the right amount of firing. 

Thorny Excrescences from Lee et al., (2013)

A recent paper from the Pak lab explains how in some specific neurons in the hippocampus (CA3 pyramidal cells), the activity of the whole cell is strongly controlled by a some very peculiar synapses. These synapses are close to the cell body, and are on these HUGE weirdly shaped spines (see above) called "Thorny Excrescences". For comparison 'normal' spines look more like this:

Spines from Lee et al. (2013)

The Thorny Excrescences (TEs) are massive spines that contain many separate synapses on them, but connect to the dendrite through 1 neck. 'Normal' spines, on the other hand, usually have 1 synapse at the spine head, and connect to the dendrite through 1 neck.

The size of the TEs, and their proximity to the soma makes them an extremely powerful way to control the signals that the soma receives. Lee et al (2013) shows that when you drastically reduce activity by blocking action potentials (using TTX), you get massive growth of these TEs, but the normal spines further away from the soma stay the same.

They test 3 things to determine whether the TEs have undergone homeostatic plasticity. They look at the morphology (they are bigger), the activity (the electrical signals from them are bigger) and the molecular signatures (the molecules indicative of new synapses are more plentiful). The paper is a really nice complete story showing that these TEs have a lot of control over the general activity of the cell.

It also solves an important problem with homeostatic plasticity. That is, how can the general activity of the cell be modulated without the specific differences between synapses being erased, and consequently the memories or pieces of information they encode? If homeostatic plasticity occurs at spines dedicated to it, then the other spines can still encode specific signals while the activity of the cell as a whole changes.

© TheCellularScale



Lee KJ, Queenan BN, Rozeboom AM, Bellmore R, Lim ST, Vicini S, & Pak DT (2013). Mossy fiber-CA3 synapses mediate homeostatic plasticity in mature hippocampal neurons. Neuron, 77 (1), 99-114 PMID: 23312519

The Inadvertent Psychological Experiment

Escape from Camp 14 is deeply disturbing, and I highly recommend it.

Escape from Camp 14 by Blaine Harden

Escape from Camp 14 is a chilling tale of Shin Dong-hyuk's escape from a North Korean prison camp. What is so interesting about Shin Dong-hyuk's story as written by Blaine Harden is that he was born inside this North Korean prison camp. Apparently they allow breeding between prisoners as a reward for 'good behavior.'

Escape from Camp 14 reveals the obscene violations of human rights that occur in North Korean prison camps, and was especially poignant because I am a similar age to Shin Dong-hyuk and could directly compare my memories during the specified years to his. For example he escapes on January 2nd, 2005 and I couldn't help but think of the New Years party I was at that year and how absurdly different my life has been from his.

This book struck me in a way that reading about the horrors of the Holocaust never could. Those atrocities happened long before I was born. But the atrocities in North Korea are happening right now. I mean right this minute in a prison camp, a child is likely being beaten, a woman is likely being raped by a guard (later to be killed if she happens to become pregnant), someone may be picking undigested corn kernels from cow dung to ease hir starving belly, and maybe two lucky prisoners are getting to have 'reward breeding' time. Right now. This minute. That is just nuts.

The other thing that struck me about this whole situation is that having children born into a hostile prison environment is an inadvertent psychological experiment. These children are raised without love and without trust. One of the sharpest points in the book is the reveal that Shin Dong-hyuk turned his own mother and brother in to the guards for planning an escape. He watched his mother's execution shortly thereafter and felt nothing but anger at her for planning an escape.

When he finally escaped, it was shocking to him to see people talking and laughing together without guards coming over to (violently) stop it. In Camp 14, gathering of more than 2 people was forbidden. These prison children are being raised on fear of the guards and suspicion of each other. One of the easiest ways to be rewarded is to tattle on another prisoner for something (stealing food, for example), and the children learn this quickly.

If something drastic happens and North Korea dissolves, these children raised in prison camps will have a near impossible time trying to adjust to a life of freedom and will have a difficult time forming attachments and trusting others (as seen in Shin Dong-hyuk and other refugees from North Korea). Their personalities and psychological profiles could be fundamentally different from any other group on earth. These atrocities should be stopped and these people should be studied and rehabilitated.

© TheCellularScale


Lee YM, Shin OJ, & Lim MH (2012). The psychological problems of north korean adolescent refugees living in South Korea. Psychiatry investigation, 9 (3), 217-22 PMID: 22993519

Everyone should learn everything.

Today I am getting on a bit of a soapbox about things.  Specifically about things scientists should learn.

Scientists should learn everything (source)

In an ideal world everyone would be good at everything, but as you have probably noticed this is NOT the case. Some people are good at lots of things and some people are really good at specific things, but terrible at others, and some unfortunate people are generally bad at a lot of things and mediocre at a few.

Recently, I've been hearing increasing noise for scientists (or scientists-in-training) to learn X, Whatever X is. 'Scientists should learn art"; "Scientists should learn creative writing"; "Scientists should learn how to communicate to the public more clearly" ; "Scientists should learn managerial skills" and so forth.

This bothers me for a couple of reasons.

1. Why should the scientists learn all this stuff? Why aren't people clamoring for artists to learn microbiology, or for novelists to brush up on their molecular genetics?

and

2. What is wrong with some people being good at science and NOT being good at much else?

Yes, if waving a magic wand could suddenly make scientists good communicators, artists, and managers, I wouldn't object. But these things (like science itself) take training. And god knows, graduate students already get a lot of training.

And yes, running a lab takes managerial skills and grant writing requires clear communication and story-telling skills. But instead of requiring one person to be good at all these things, why not divide up the labor a little and have a 'lab manager' help run the lab, and a 'departmental grants guru' to help polish the grants.

It is really easy to say 'scientists should learn X' because...

1. there is a perception that scientists are smart and can learn things easily

and

2. it is always impossible to argue that things wouldn't be better if scientists were good at X. (Wouldn't it be great if all scientists were excellent public speakers? yes of course.)

The problem is implementing the extensive training in X that a scientist should have, and what current training to replace. Therefore I propose that the 'scientists should learn X' statements should all be adjusted to say 'scientists should get extensive training in X rather than Y'.

© TheCellularScale

a STORM inside a cell

We've been talking about some of the most cutting edge intracellular visualization techniques lately. Array tomography and Serial block-face electron microscopy have been featured. Today we'll talk about STORM imaging.

STORM imaging (Xu et al., 2013)

STORM stands for Stochastic Optical Reconstruction Microscopy. While Array tomography and Serial block-face EM are both revolutionary in that they can combine very high resolution imaging with relatively large volumes of tissue, STORM is an advancement that lets you see tiny tiny little molecules within the cell.

The problem with 'normal' imaging is that molecules are smaller than the diffraction of light.

Example of the STORM resolution (from Zhuang lab's webpage)

In the figure above, imaging some tiny molecules next to each other is impossible with traditional fluorescence microscopy, but with STORM, you can resolve 10s of nanometers (nm).

To do this, STORM uses photoswitchable dyes, which means that the dye can be turned on or off. This allows researchers to turn on tiny little areas and then turn them off. If all the dye is turned on all at once, the image will look like a big mess because the signals will all overlap each other. But turning on only a few at a time allows you to estimate where the actual protein or molecule is.

"The imaging process consists of many cycles during which fluorophores are activated, imaged, and deactivated. In each cycle only a subset of the fluorescent labels are switched on, such that each of the active fluorophores is optically resolvable from the rest. This allows the position of these fluorophores to be determined with nanometer precision." -Zhuang lab webpage

So what amazing things can they do with this STORM?
A recent paper by Xu et al. (2013) found that the actin which plays a huge role in the intracellular structure of a neuron, has a specific ring-like structure along the axons.

Xu et al., 2013 Figure 4F

This is the kind of research that will immediately go into neuroscience and cell biology textbooks. Xu et al. discovered how actin was structured along the axon simply by being able to 'see it'.

Not only did they discover the structure of actin and spectrin (magenta above) in the axon, but they also found some other interesting molecular patterns that appear to relate to the actin ring structure. The sodium channels, which control action potential propagation down the axon, are concentrated about half way between the ends of the spectrin tetramers. The potential for super-resolution microscopy like STORM is huge. The location of molecules with relation to one another probably plays a huge role in the function of cells and now we have the tools to map them.

© TheCellularScale



Xu K, Zhong G, & Zhuang X (2013). Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons. Science (New York, N.Y.), 339 (6118), 452-6 PMID: 23239625

LMAYQ: Mirror Neurons

Mirror neurons really excite people. They've been hyped as the root of empathy and essential to human nature. I've addressed some of this hype, but questions remain. So for this edition of Let Me Answer Your Questions, we will focus on mirror neurons. As always, the LMAYQ series can be found here.

Escher's Mirror (source)

1. "What do mirror neurons look like?" 
Good question, and guess what? I have addressed this directly.

2. "Do mirror neurons fire when you die?"
Another good question. Ultimately, all neurons stop firing when you die including mirror neurons. But this doesn't happen immediately. In fact, if the death is due to something traumatic such as decapitation, the neurons might fire more when the nerves are severed between the spinal cord and the brain. But this just brings up questions about the moment of death. Is it when the heart stops, the head is severed? or is it when the neurons stop firing? Can a 'person' be dead when some of their cells are still alive?

In a lot of cellular-level research, cells are kept alive after the animal that they came from has died. Electrophysiologists keep slices of brain alive for hours to record electrical signals from their neurons. Still other projects involve culturing neurons that have been extracted from an animal. These neurons are carefully tended for days, weeks, and even months. These neurons not only stay alive in little dishes, but they can also grow and even control robots.

There are living neurons in there (source)

3. "what does it mean to have a mirrored brain?"
Well. nothing really. I have never heard the term 'mirrored brain' before, and it sounds like something that might be in a pseudo-scientific quiz along the lines of Are you left brained or right brained?  "Do you have a mirrored brain? take our quiz and find out"

4. "Is love nothing but mirror cells?"
I love and hate these kinds of questions. The idea that love is nothing if it can be explained by a biological mechanism really gets me. If love is just neurons firing (mirror or otherwise), so what? Why would that make LOVE any less meaningful?

Heart Mirror (source)

On the other hand, this is a really interesting question if it is asking whether mirror neurons have anything to do with love. Again mirror neurons are neurons that fire when you do something and also when you see someone else do that thing. Specifically, they were discovered in monkeys when monkeys reached for something and then saw other hands reach for something. Then the concept got hyped up. It's easy to imagine that if you have neurons that fire when you do something and when you see some one else do that same thing, that those might have something to do with 'feeling another's pain' and thus empathy. So it's not a huge step to take from there to think that maybe mirror neurons could have something to do with building relationships and love.

But the speculation here is WAY beyond the science. There isn't good solid evidence for mirror neurons controlling empathy, and certainly not for being the basis of love.

 © TheCellularScale

Connecting Form and Function: Serial Block-face EM

The retina is a beautiful and wondrous structure, and it has some really weird cells.

Retina by Cajal (source)

Retinal Ganglion Cells (RGC) have all sorts of differentiating characteristics. Some are directly sensitive to brightness (like rods and cones), while some are sensitive to the specific direction that a bar is traveling.

I am discussing really amazing new techniques to see inside cells this month, and have already posted about the magic that is Array Tomography. Today we'll look at another amazing new technique that (like array tomography) combines nano-scale detail with a scale large enough to see many neurons at once. This technique is called Serial Block-face Electron Microscopy (SBEM), and was recently used to investigate how starburst amacrine cells control the direction-sensitivity of  retinal ganglion cells.

Serial Block-face EM (source)

SBEM images are acquired by embedding a piece of tissue (like a retina) in some firm substance and slicing it superthin (like 10s of nanometers thick) with a diamond blade. The whole slicing apparatus is set up directly under a scanning electron microscope, so as soon as the blade cuts, an image is taken of the surface remaining. Then another thin slice is shaved off and the next image is taken, and so on.

Using this technique, Briggman et al. (2011) are able to trace individual neurons and their connections for a (relatively) large section of retina. What is so great about this paper is that before they sliced up the retina, they moved bars around in front of it and measured the directional selectivity of a bunch of neurons. Then, using blood vessels and landmarks to orient themselves, they were able to find the exact same cells in the SBEM data and trace them.

Briggman et al. (2011) Fig1C: Landmark blood vessels

The colored circles above represent the cell bodies and the black 'tree' shape are the blood vessel landmarks.

Once they found the cell bodies, the could trace the cells through the stacks of SBEM data. What is really neat is that you can try your hand at this yourself. This exact data set has been turned into a game called EYEWIRE by the Seung lab at MIT.

Reconstructing the cells, they could not only tell which cells connected to which other cells, but they could also see exactly where on the dendrites the cells connected. This is the really amazing part. They found that specific dendritic areas made synapses with specific cells.

Briggman et al. (2011) Fig4: dendrites as the computational unit

This starburst amacrine cell overlaps with many retinal ganglion cells (dotted lines represent the dendritic spread of individual RGCs)...BUT its specific dendrites (left, right, up down etc) synapse selectively onto RGCs sensitive to a particular direction. Each color represents synapses onto a specific direction-sensitivity. e.g. yellow dots are synapses from the amacrine cell onto RGCs which are sensitive to downward motion.

This suggests that each individual dendritic area of these starburst amacrine cells inhibits (probably) a specific type of RGC, and that these dendrites act relatively independently of one another.

"The specificity of each SAC dendritic branch for selecting a postsynaptic target goes well beyond the notion that neuron A selectively wires to neuron B, which is all that electrophysiological measurements can test. Instead the dendrite angle has an additional, perhaps dominant, role, which is consistent with SAC dendrites acting as independent computational units."  -Briggman et al (2011)(discussion)

These cells are weird for so many reasons, but the ability of the dendrites to act so independently of one another is a new and exciting development that I hope to see more research on soon.

© TheCellularScale



Briggman KL, Helmstaedter M, & Denk W (2011). Wiring specificity in the direction-selectivity circuit of the retina. Nature, 471 (7337), 183-8 PMID: 21390125

Van Gogh was afraid of the moon and other lies

I remember the first time I realized just how easily false information gets spread about.

A terrifying starry night

I was in French class in high school. Our homework had been to find out 1 interesting fact about Van Gogh and tell it to the class. When it was my turn, I said some boring small fact that I no longer remember. My friend sitting behind me, however, had a fascinating fact: When Van Gogh was a young child, he was actually afraid of the moon.

The teacher and the class were all quite impressed and thought about how interesting that was and how that fact might be reflected in the way that he paints the Starry Night. Though this fact was new to everyone, including the teacher, no one even thought to question its truth.

In fact, the teacher was so enthralled by this idea that she passed the information on to all the other French classes that day.

When talking to my friend later that day, he admitted that he had not done the assignment, and just made the 'fact' up. I was completely surprised, not only that someone had not done their homework *gasp*, but that I hadn't even thought to question whether this was true or not. 

The best lies have an element of truth (source)

 Misinformation like this spreads like wildfire and is exceptionally difficult to undo. The more things you can link this piece of information to in your brain, the more true you might think it and even after your learn that it's not true, you still might inadvertently believe it or fit new ideas into the context it creates. Myths like the corpus callosum is bigger in women than in men is just one of those things that is easy to believe.

An interesting paper by Lewandowsky et al. (2012) explains how this kind of persistent misinformation is detrimental to individuals and to society with the example of vaccines causing autism. This particular piece of misinformation is widely believed to be true despite numerous attempts to publicize the correct information and the most recent scientific findings showing no evidence for a link between the two. 

The authors of this paper give some recommendations for making the truth more vivid and effectively replacing the misinformation with new, true information. For example:

"Providing an alternative causal explanation of the event can fill the gap left behind by retracting misinformation. Studies have shown that the continued influence of misinformation can be eliminated through the provision of an alternative account that explains why the information was incorrect." Lewandowsky et al. (2012)

Misinformation can be replaced with information, but it takes more work to replace a 'false fact' than to just have the truth out there in the first place. It is much better when misinformation is not spread around in the first place, than when it is retroactively corrected.

This paper is also covered over at The Jury Room.


© TheCellularScale



Lewandowsky, S., Ecker, U., Seifert, C., Schwarz, N., & Cook, J. (2012). Misinformation and Its Correction: Continued Influence and Successful Debiasing Psychological Science in the Public Interest, 13 (3), 106-131 DOI: 10.1177/1529100612451018